An in vitro model was developed to study the multistage progression in malignancy of human bronchial epithelial cells that were transformed to immortal cell lines with measureable malignant potential following transfection with Harvey ras oncogene (v-Ha-ras). Progressively malignant cell lines derived from this transformation were selected by continued growth in tissue culture (TBE-1), anchorage-independent growth in soft agar (TBE-1SA), and xenogenic transfer of TBE-series tumor tissues between mice. The TBE-1SA cell line has a shorter average latency period for subcutaneous primary tumors in athymic nude mice, higher frequency of successful transplantation, and more frequent metastasis to the liver, spleen, and lungs from primary tumors than tumorigenic cell lines selected for progression by continued growth in cell culture. The secondary growth of tumors that were passaged between mice also led to increased malignancy for each type of TBE-cell line tested. Tumors from TBE cell lines have a similar array of histologic morphologies, and decreased expression of histocompatibility markers (HLA class I) were less prevalently expressed by tumor cells than those cell lines that were most tumorigenic. The karyotypic variation and complex pattern of surface markers observed in different TBE cell lines and tumor tissue is consistent with an increasing adaptive change that alters the expression of multiple genes during malignant progression. Mechanistically, this is consistent with increased adaptation by cell populations derived from v-Ha-ras transformed human epithelial cells that progress to malignancy and metastasis.